Full-dose radiation therapy by megavoltage beams has yielded poor results for invasive bladder cancer (only 30-50% cured). This has required clinicians to recommend cystectomy, with its associated major losses of genitourinary function, to patients with muscle-invading tumors even though the cure rate is still less than 50%. Recent innovations using combined modality therapy (transurethral surgery, radiation and chemotherapy) indicate, preliminarily, improved results (60% of patients have intact bladders that are tumor-free). However, no known objective tumor characteristic yet exists at the time of diagnosis that is a clinically satisfactory predictor for success by such bladder-sparing treatments. The care of individual patients would be sharply improved were such a prognostic factor identified. The MGH Urologic Oncology Group has treated 115 patients with invasive bladder cancer on prospective clinical trials using these combined modalities. This represents a large patient population with a uniform tumor inception cohort, with complete or ongoing follow up, with 70% bladder preservation, and with initial tumor specimens available with full histopathologic subtyping and DNA cytometry. Alterations of tumor suppressor genes have been implicated to play a significant role in the pathogenesis of many forms of cancer and may correlate with certain malignant characteristics. The main research goal of MGH Urologic Oncology-Molecular Biology Research Group is to investigate the role of tumor suppressor genes in urologic cancers. We have established over the past 8 months the needed laboratory techniques and have integrated this clinical-basic science team to evaluate p53 gene (exone 5-8) alterations on frozen and fixed paraffin-embedded archival bladder tumor specimens. Our objective of the proposed research is to determine whether alterations of the two best characterized tumor suppressor genes, RB and p53, will correlate with radiation response and/or other aspects of treatment outcome. We envision this as a first step in a systemic approach to the genetic analysis of the pathogenesis of bladder cancer. We judge our laboratory technology, the available archival initial tumor specimens and our strong system of clinical and statistical analysis of patient outcome all indicate that this short-term research project to correlate tumor suppressor gene alterations with radiotherapy and chemotherapy response will be completed and will provide solid new information, whatever the outcome.